A longstanding issue in environmental health is the need to understand the role the environment plays in human brain development. The brain of the neonate is particularly susceptible to disruption of the sensory environment, which can have profound effects on its physiology and morphology. Such susceptibility of the developing brain to environmental influence by sensory manipulation or to environmental toxicants is particularly pronounced during defined critical periods of postnatal life. On the one hand, this susceptibility makes the developing brain particularly vulnerable to toxic insults. On the other hand, the plasticity of the connections between neurons, or synapses, is critical for refining brain circuitry during postnatal development. Similar mechanisms for changing synapses are likely to serve the basis for learning in the adult. Our primary interest, therefore, has been to determine the molecular basis of long-lasting synaptic plasticity. Toward our goal of learning how neuronal activity can induce lasting modifications in neurons, we use a diverse collection of molecular, biochemical, electrophysiological, and imaging techniques. We use the hippocampal slice preparation from neonate and adult rodents. The relatively simple laminar structure of the hippocampus, which itself plays an important role in learning and memory, allows electrophysiological studies to be performed easily. To measure synaptic responses, we use techniques that include whole-cell patch clamp recordings and field potential recordings from hippocampal slices either acutely prepared or cultured. To determine how transcription is regulated by neuronal activity, we use molecular and biochemical methods with acutely dissociated hippocampal and cortical neuronal cell cultures, which can be stimulated pharmacologically to mimic long-term potentiation (LTP) and long-term depression (LTD). To understand how synaptic changes persist for up to a lifetime, we study how neuronal activity regulates gene transcription to consolidate synaptic changes, and microscopy to investigate structural changes.In addition, we now use in vivo recording techniques to address the role of the different hippocampal subregions in specific behaviors. To investigate how experience shapes neuronal connections, we sought to determine how synaptic plasticity in the form of LTD might lead to activity-dependent pruning of synaptic contacts. Although there is compelling evidence that shrinkage of dendritic spines coincides with LTD, and that LTD is accompanied by synapse loss, whether NMDA receptor (NMDAR)-dependent LTD is a required step in the progression toward synapse pruning is still unknown. Using repeated applications of NMDA to induce LTD in dissociated rat neuronal cultures, we found that synapse density, as measured by colocalization of fluorescent markers for pre- and postsynaptic structures, was decreased. Furthermore, synapse loss was unlikely to require direct contact with microglia, as the number of these cells was minimal in our culture preparations. Supporting a model by which NMDAR-LTD is required for synapse loss, the effect of NMDA on fluorescence colocalization was prevented by phosphatase and caspase inhibitors. In addition, gene transcription and protein translation also appeared to be required for loss of putative synapses. These data support the idea that NMDAR-dependent LTD is a required step in synapse pruning and contribute to our understanding of the basic mechanisms of this developmental process. One approach that we have taken to gain insight into the mechanisms of synaptic plasticity has been to compare highly plastic brain areas, such as the CA1 area of hippocampus, with less plastic areas. From the expression pattern of some genes, we predicted and found that one area of the hippocampus, the CA2, would have a resistance to synaptic plasticity including LTP and LTD, even though we found that synaptic responses in CA2 were very similar to those in the neighboring CA1 and CA3 areas. We later established that dendritic spines in CA2 have very different calcium dynamics from spines in CA1 and CA3 in that both calcium buffering capacity and rates of calcium extrusion were higher in CA2 spines when compared with those in the neighboring regions. In addition, we have found that a regulator of G-protein signaling (RGS-14), and adenosine A1 receptors (A1Rs), which are highly enriched in CA2, are also negative regulators of plasticity in CA2. Recently, we have also found that the social neuropeptides oxytocin and vasopressin act to induce synaptic potentiation in CA2 pyramidal neurons in a way that closely resembled typical LTP. The vasopressin 1b receptor (avpr1b) is highly enriched in CA2 neurons over all other parts of the brain, suggesting that CA2 may play an important role in social behavior; recent work in other laboratories support this view. Using information we learn from CA2, we also aim to determine the nature of the developmental down-regulation of synaptic plasticity in the form of critical periods and how plasticity is modulated in different brain areas. Recently, we have found that a specialized extracellular matrix, called perineuronal nets (PNNs), play a role in limiting synaptic plasticity in area CA2. We found that in mouse CA2, PNNs surround pyramidal (excitatory) neurons and their excitatory synapses on dendritic spines. Importantly, we found that staining for PNNs increases during postnatal development and could be modified by early-life enrichment. Because PNNs had been previously implicated in limiting synaptic plasticity late in postnatal development, effectively ending critical periods for plasticity, we tested whether PNNs also play an important role in restricting synaptic potentiation of the normally plasticity-resistant excitatory CA2 synapses. We found that treatment of hippocampal slices with an enzyme that disrupts PNNs enables synaptic potentiation in CA2 pyramidal neurons. CA2 and its surrounding regions are anatomically an molecularly very similar, and as such, these findings may therefore lead to identification of other critical molecular components in the pathways necessary for developmental changes in synaptic plasticity and development of normal cognition. Furthering this aim, we have optimized a method for obtaining high-quality mRNA from specific hippocampal subregions using laser capture microdissection. Prior to our work on synaptic plasticity in area CA2, few groups had appreciated that the area was in fact a distinct region of the hippocampus and as a result, nothing was known about the how neurons in area CA2 function during even the simplest of behaviors such as exploration of an open field. We therefore set out to record CA2 neurons in vivo in rats during exploration and social interactions. We found that similar to neurons in area CA1, neurons in CA2 fired action potentials when the animal traversed particular places in the environment, i.e. place fields. However, the neurons place fields were extremely sensitive to the presence of another animal or a novel object in that they often lost some place fields and gained others. We interpret this finding to indicate that CA2 neurons are uniquely sensitive to changes in social context and other situations involving novelty, suggesting that neurons in this area may be providing downstream regions with information relevant to changes in context. As increasing evidence is implicating area CA2 in several types of rodent social behavior, these findings have relevance to human psychiatric disorders such as autism and schizophrenia that manifest with deficits in social cognition. Together with our studies on the cellular mechanisms underlying synaptic plasticity, these studies will give us a better understanding of how experience during development shapes brain circuitry.